ATF2 (activating transcription factor 2)

2012-10-01   Jean-Loup Huret 




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ATF2 gene structure based on data available in the Ensembl release 44. Upstream non-coding exons (green). Coding exons (pink), 3 untranslated sequence (red). The size of the exons in nucleotides is indicated below each exon. Exon number is indicated within the exon.


Gene size: 96 Kb.


Initiation codon located in exon 3. Normal message is 1518 nucleotides. Numerous splice variants (24 according to Ensembl). A small isoform of ATF2, ATF2-small (ATF2-sm), with a calculated mass of 15 kDa, has no histone acetyltransferase (HAT) activity, but, still, has the ability to bind CRE-containing DNA. ATF2-sm is only composed of the first two and last two exons of ATF2. Within the body of the uterus, ATF2 full length is expressed only in the lower segment, whereas there is a gradient of expression of the ATF2-sm protein with the highest level in the upper segment. A significant number of genes are differentially regulated by the ATF2-fl and ATF2-sm transcription factors (Bailey et al., 2002; Bailey and Europe-Finner, 2005).


Atlas Image


ATF2 is one of 16 members of the ATF and CREB group of bZIP transcription factors, components of the activating protein 1 (AP-1). The canonical form of ATF2 is made of 505 amino acids, 54.537 kDa according to Swiss-Prot. ATF2 comprises from N-term to C-term a zinc finger (C2H2-type; DNA binding) (amino acids 25-49), a transactivation domain (aa 19-106, Nagadoi et al., 1999), two proline-rich domain, (involved in protein-protein interaction) (Pro202, 207, 210, 212, 214, 216, 222, 228, 231 and 243, 247, 251, 256, 259, 261, 263, 267, 269), two glutamine-rich domains (involved in transcriptional trans-activation) (Gln268, 271, 284, 285 and 306, 313, 316, 317), a basic motif (amino acids 351-374), and a leucine zipper domain (amino acids 380-408, and a nuclear export signal), making a basic leucine zipper required for dimerization, and involved in CRE-binding (Kara et al., 1990 and Swiss-Prot.). ATF2 contains two canonical nuclear localization signals (NLS) in its basic motif, and two nuclear export signal (NES) in its leucine zipper, one of which in N-term: (1)MKFKLHV(7) (Liu et al., 2006; Hsu and Hu, 2012).


Ubiquitously expressed. High expression in brain and in regenerating liver (Takeda et al., 1991).


Cytoplasmic and nuclear protein. The nuclear transport signals (NLS and NES) contribute to the shuttling of ATF2 between the cytoplasm and the nucleus. ATF2 homodimers are localized in the cytoplasm, and prevent its nuclear import. Heterodimerization with JUN prevents nuclear export of ATF2. JUN-dependent nuclear localization of ATF2 occurs upon stimulating conditions (retinoic acid-induced differentiation and UV-induced cell death) (Liu et al., 2006). Phosphorylation of ATF2 on Thr52 by PRKCE (PKCE) promotes its nuclear retention and transcriptional activity (Lau et al., 2012). Stress- or damage-induced cytosolic localization of ATF2 could be associated with cell death (Lau and Ronai, 2012). When ATF2 translocates to the cytoplasm, it localizes at the mitochondrial outer membrane (Lau et al., 2012).


- ATF2 is a transcription factor. ATF2 forms a homodimer or a heterodimer with JUN (Hai and Curran, 1991), or other proteins (see below).
- Typically, it binds to the cAMP-responsive element (CRE) (consensus: 5-GTGACGT[AC][AG]-3), a sequence present in many cellular promoters (Hai et al.,1989). However, depending on the heterodimeric partner, ATF2 binds to different response elements on target genes. ATF2/JUN and ATF2/CREB1 bind the above noted concensus sequence. ATF2 is mainly a transcription activator, but it also may be a transcription repressor (reviews in Bhoumik and Ronai, 2008; Lopez-Bergami et al., 2010; Lau and Ronai, 2012).

Activation of ATF2
ATF2 is activated by stress kinases, including JNK (MAPK8, MAPK9, MAPK10) and p38 (MAPK1, MAPK11, MAPK12, MAPK13, MAPK14) and is implicated in transcriptional regulation of immediate early genes regulating stress and DNA damage responses (Gupta et al., 1995; van Dam et al., 1995) and cell cycle control under normal growth conditions.(up-regulation of the CCNA2 (cyclin A) promoter at the G1/S boundary) (Nakamura et al., 1995). In response to stimuli, ATF2 is phosphorylated on threonine 69 and/or 71 by JNK or by p38. Phosphorylation on Thr69 and Thr71 of ATF2 and its dimerization are required to activate ATF2 transcription factor activity. Phosphorylation on Thr69 occurs through the RALGDS-SRC-P38 pathway, and phosphorylation on Thr71 occurs through the RAS-MEK-ERK pathway (MAPK1, MAPK3 (ERK1), MAPK11, MAPK12 and MAPK14) (Gupta et al., 1995; Ouwens et al., 2002).
The intrinsic histone acetylase activity of ATF2 promotes its DNA binding ability (Abdel-Hafiz et al., 1992; Kawasaki et al., 2000).
Interaction of ATF2 with CREBBP (CREB-binding protein, also called p300/CBP) is dependent upon phosphorylation at Ser121 induced by PRKCA. ATF2 and CREBBP cooperate in the activation of transcription (Kawasaki et al., 1998; Yamasaki et al., 2009).
VRK1 activates and stabilizes ATF2 through direct phosphorylation of Ser62 and Thr73 (Sevilla et al., 2004).

Down regulation of ATF2
Among other down regulation mechanisms, ATF2 is down regulated, by MIR26B in response to ionizing radiation (Arora et al., 2011).
Transcriptionally active dimers of ATF2 protein are regulated by ubiquitylation and proteosomal degradation (Fuchs et al., 1999); phosphorylation of ATF2 on Thr69 and Thr71 promotes its ubiquitylation and degradation (Firestein and Feuerstein, 1998).
A cytoplasmic alternatively spliced isoform of ATF7, ATF7-4, is a cytoplasmic negative regulator of both ATF2 and ATF7. It impairs ATF2 and ATF7 phosphorylation (ATF7-4 indeed sequesters the Thr53-phosphorylating kinase in the cytoplasm, preventing Thr53 phosphorylation of ATF7) and transcriptional activity (Diring et al., 2011).
The activity of ATF2 is repressed by an intramolecular interaction between the N-terminal domain and the b-ZIP domain (Li and Green, 1996). The N-terminal nuclear export signal (NES) of ATF2 negatively regulates ATF2 transcriptional activity (Hsu and Hu, 2012).

Dimerization of ATF2
The basic leucine zipper (basic motif + leucine zipper, "b-ZIP") of ATF2 enables homo- or hetero-dimerization.
The main dimerization partners of ATF2 are the following: ATF2, BRCA1, CREB1, JDP2, JUN, JUNB, JUND, MAFA, NF1, NFYA, PDX1, POU2F1, TCF3 (Lau and Ronai, 2012).
ATF2 homodimers have a low transcriptional activity.
MAPKAP1 (SIN1) binds to the b-ZIP region of ATF2, and also binds MAPK14, and is required for MAPK14-induced phosphorylation of ATF2 in response to osmotic stress, and activates the transcription of apoptosis-related genes (Makino et al., 2006).
In response to stress, ATF2 binds to POU2F1 (OCT1), NFI, and BRCA1 to activate transcription of GADD45. The b-Zip region of ATF2 is critical for binding to BRCA1. ATF2 also binds and activates SERPINB5 (Maspin) (Maekawa et al., 2008).
ATF2 also forms a heterodimer with JDP2, a repressor of AP-1. JDP2 inhibits the transactivation of JUN by ATF2 (Jin et al., 2002).

ATF2 target genes
Under genotoxic stress, a study showed that 269 genes were found to be bound by ATF2/JUN dimers. Immediate-early genes were a notable subset and included EGR family members, FOS family members, and JUN family members, but the largest group of genes belonged to the DNA repair machinery (Hayakawa et al., 2004, see below).
Among the ATF2 target genes are :
- Transcription factors, such as JUN, ATF3, DDIT3 (CHOP), FOS, JUNB,
- DNA damage proteins (see below),
- Cell cycle regulators (CCNA2, CCND1), see below,
- Regulators of apoptosis (see below and Hayakawa et al., 2004),
- Growth factor receptors and cytokines such as PDGFRA (Maekawa et al., 1999), IL8 (Agelopoulos and Thanos, 2006), FASLG (Fas ligand), TNF (TNFalpha), TNFSF10 family (Herr et al., 2000; Faris et al., 1998),
- Proteins related with invasion such as MMP2 (Hamsa and Kuttan, 2012) and PLAU (UPA): ATF2/JUN heterodimer binds to and activates PLAU (De Cesare et al., 1995),
- Cell adhesion molecules, such as SELE, SELP, and VCAM1 (Reimold et al., 2001),
- Proteins engaged in the response to endoplasmic reticulum (ER) stress. ATF2/CREB dimers bind the CRE-like element TGACGTGA of HSPA5 (Grp78) and activates it (Chen et al., 1997),
- Genes encoding extracellular matrix components seem to constitute an important subset of ATF2/JUN-target genes (van Dam and Castellazzi, 2001).
- PTEN, a negative regulator of the PI3K/AKT signaling pathway, is positively regulated by ATF2 (Qian et al., 2012).
- ATF1 and ATF2 regulate TCRA and TCRB gene transcription.

Histones, Chromatin
UV treatment or ATF2 phosphorylation increases its histone acetyltransferase (HAT) activity as well as its transcriptional activities. Lys296, Gly297 and Gly299, are essential both for histone acetyltransferase activity and for transactivation (Kawasaki et al., 2000).
Binding of ATF2 to the histone acetyltransferase RUVBL2 (TIP49b) suppresses ATF2 transcriptional activity. RUVBL2s association with ATF2 is phosphorylation dependent and requires amino acids 150 to 248 of ATF2 (Cho et al., 2001).
ATF2 interacts with the acetyltransferase domains of CREBBP. ATF2 b-ZIP could serve as an acetyltransferase substrate for the acetyltransferase domains of CREBBP. ATF2 is acetylated on Lys357 and Lys374 by CREBBP, which contributes to its transcriptional activity (Karanam et al., 2007).
ATF2 and ATF4 are essential for the transcriptional activation of DDIT3 (CHOP) upon amino acid starvation.
ATF2 is essential in the acetylation of histone H4 and H2B, and thereby may be involved in the modification of the chromatin structure. An ATF2-independent HAT activity is involved in the amino acid regulation of ASNS transcription (Bruhat et al., 2007).
The histone variant macroH2A recruitement into nucleosomes could confer an epigenetic mark for gene repression. The constitutive DNA binding of the ATF2/JUND heterodimer to the IL-8 enhancer recruits macroH2A-containing nucleosomes in B cells, thus inhibiting transcriptional activation (Agelopoulos and Thanos, 2006).
Heat shock or osmotic stress induces phosphorylation of dATF2 (ATF2 in Drosophila), results in its release from heterochromatin, and heterochromatic disruption. dATF2 regulates heterochromatin formation. ATF2 may be involved in the epigenetic silencing of target genes in euchromatin. The stress-induced ATF2-dependent epigenetic change was maintained over generations, suggesting a mechanism by which the effects of stress can be inherited (Seong et al., 2011).

DNA damage response
Phosphorylation on Ser490 and Ser498 by ATM is required for the activation of ATF2 in DNA damage response. Phosphorylation of ATF2 results in the localisation of ATF2 in ionizing radiation induced foci (in cells exposed to ionizing radiation (IR), several proteins phosphorylated by ATM translocate and colocalize to common intranuclear sites. The resulting IR-induced nuclear foci (IRIF) accumulate at the sites of DNA damage). ATF2 expression contributes to the selective recruitment of MRE11A, RAD50, and NBN (NBS1) into IRIF. ATF2 is required for the IR-induced S phase checkpoint, and this function is independant of its transcriptional activity (Bhoumik et al., 2005).
KAT5 (TIP60) is a histone acetyltransferase and chromatin-modifying protein involved in double strand breaks (DSB) repair, interacting with and acetylating ATM. ATF2 associates with KAT5 and RUVBL2. Under non-stressed conditions, ATF2 in cooperation with the ubiquitin ligase CUL3 promotes the degradation of KAT5 (Bhoumik et al., 2008a).
Following genotoxic stress, 269 genes were found to be bound by ATF2/JUN dimers (see above), of which were 23 DNA repair or repair-associated genes (ERCC1, ERCC3, XPA, MSH2, MSH6, RAD50, RAD23B, MLH1, HIST1H2AC, PMS2, FOXN3 (CHES1), LIG1, ERCC8 (CKN1), UNG, XRCC6 (G22P1), TREX1, PNP, GTF2H1, ATM, FOXD1, DDX3X, DMC1, and the DNA repair-associated GADD45G), derived from several recognized DNA repair mechanisms (Hayakawa et al., 2004).

Cell Cycle
RB1 constrains cellular proliferation by activating the expression of the inhibitory growth factor TGFB2 (TGF-beta 2) through ATF2 (Kim et al., 1992).
CREB1 dimerizes with ATF2 to bind to the CCND1 (cyclin D1) promoter, to increase CCD1 expression (Beier et al., 1999).
JUND dimerizes with ATF2 to repress CDK4 transcription, a protein necessary for the G1-to-S phase transition during the cell cycle, by binding to the proximal region of the CDK4-promoter, contributing to the inhibition of cell growth. The physical interactions of ATF2 with JUND implicates the b-ZIP domain of ATF2 (Xiao et al., 2010).
Heterodimerization of JUND with ATF2 activates CCNA2 (cyclin A) promoter. CCNA2 is essential for the control at the G1/S and the G2/M transitions of the cell cycle. In contrast, ATF4 expression suppresses the promoter activation mediated by ATF2 (Shimizu et al., 1998).

ATF2/CREB1 heterodimer binds to the CRE element of the BCL2 promoter (Ma et al., 2007).
ATF2 induces BAK upregulation (Chen et al., 2010).
MAP3K5 (ASK1) activates ATF2 and FADD-CASP8-BID signalling, resulting in the translocation of BAX and BAK, and subsequently mitochondrial dysregulation (Hassan et al., 2009).
ATF2/JUN heterodimers bind and activate CASP3, a key executor of neuronal apoptosis (Song et al., 2011).
Following death receptor stimulation, there is phosphorylation and binding of ATF2/JUN to death-inducing ligands promoters (FASLG, TNF, TNFSF10), which allows the spread of death signals (Herr et al., 2000). Neuronal apoptosis requires the concomitant activation of ATF2/JUN and downregulation of FOS (Yuan et al., 2009).
Many drugs are currently being tested for their ability to inhibit cell proliferation and induce apoptosis through various pathways, including ATF2 pathway.
In the cytoplasm, ATF2 abrogates formation of complexes containing HK1 and VDAC1, deregulating mitochondrial outer-membrane permeability and initiating apoptosis. This function is negatively regulated phosphorylation of ATF2 by PRKCE, which dictates its nuclear localization (Lau et al., 2012).

Metabolic control and Insulin signalling
ATF2 has been implicated in the regulation of proteins involved in metabolic control, including the control of the expression of UCP1, a protein involved in thermogenic response in brown adipose tissue (Cao et al., 2004) and phosphoenolpyruvate carboxykinase (PEPCK), a protein regulating gluconeogenesis (Cheong et al., 1998).
Insulin activates ATF2 by phosphorylation of Thr69 and Thr71 (Baan et al., 2006).
Co-expression of ATF2, MAFA, PDX1, and TCF3 results in a synergistic activation of the insulin promoter in endocrine cells of pancreatic islets. ATF2, MAFA, PDX1, and TCF3 form a multi-protein complex to facilitate insulin gene transcription (Han et al., 2011).
ATF2 target genes in insulin signalling are ATF3, JUN, EGR1, DUSP1 (MKP1), and SREBF1. Deregulation of these genes is linked to the pathogenesis of insulin resistance, beta-cell dysfunction and vascular complications found in type 2 diabetes. Therefore, aberrant ATF2 activation under conditions of insulin resistance may contribute to the development of type 2 diabetes (Baan et al., manuscript in preparation).

Iron depletion
Iron depletion induced by chelators increases the phosphorylation of JNK and MAPK14, as well as the phosphorylation of their downstream targets p53 and ATF2 (Yu and Richardson, 2011).



v-Rel-mediated transformation suggests opposing roles for ATF2 in oncogenesis. The increase in ATF2 expression observed in v-Rel-transformed cells promotes oncogenesis. On the other hand, enhanced expression of ATF2 inhibits transformation by v-Rel. ATF2 can regulate signaling pathways in a cell type-specific and/or context-dependent manner. Differences were found in the stage at which ATF2 regulated the RAS/RAF/MAPK signaling pathway in fibroblast (where it blocked the activation of RAF, MAP2K1/MAP2K2, MAPK1/MAPK3) and in the lymphoid DT40 B-cell line (where overexpression of ATF2 increased HRAS activity and phosphorylated RAF. ATF2 exhibits both oncogenic and tumor suppressor properties (Liss et al., 2010).


V258I in lung cancer cell lines (Woo et al., 2002). K105T in pancreatic cancer cell lines (Jones et al., 2008).

Implicated in

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JUNB dimerizes with either ATF2 or FOS to increased CBFB promoter activity, and further expression of MMP13, which suggests important role in neovascularization (Licht et al., 2006).
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Epithelial mesenchymal transition
Epithelial mesenchymal transition (EMT) is characterized by the loss of the epithelial cell properties and the development of mesenchymal properties of cells, with altered cytoskeletal organization and enhanced migratory and invasive potentials. EMT is seen in embryonic development, organogenesis, wound healing, and oncogenesis. TGF-beta induces EMT, and is up-regulated by ATF2 (Bakin et al., 2002; Venkov et al., 2011; Xu et al., 2012).
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Allergic asthma
In a mouse model of allergic asthma, Aspergillus fumigatus provokes the secretion TNF (TNFalpha) by A. fumigatus-activated macrophages. In response to TNF, ATF2/JUN, RELA/RELA (p65/p65) and USF1/USF2 complexes are recruited to the PLA2G4C enhancer in lung epithelial cells (Bickford et al., 2012).
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Autoimmune diseases
SMAD3 and ATF2 are activated during Theilers virus (TMEV) infection (which may provoke an autoimmune demyelinating disease). SMAD3 and ATF2 activate IL-23 p19 promoter (Al-Salleeh and Petro, 2008). IL-23 consists of a p40 subunit IL12B coupled to the p19 subunit IL23A, and has an essential role in the development of T cell-mediated autoimmune diseases (Inoue, 2010).
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Vascular homeostasis
CD39 is a transmembrane protein expressed on the surface of vascular and immune cells. CD39 inhibits platelet activation, maintains vascular fluidity, and provides protection from both cardiac and cerebral ischemia and reperfusion injuries. cAMP regulates CD39 expression through ATF2, which binds a CRE-like regulatory element lying 210 bp upstream of the CD39 transcriptional start point (Liao et al., 2010).
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Bone development
ATF2 promotes chondrocyte proliferation and cartilage development through CCND1 upregulation in chondrocytes (Beier et al., 1999); mice carrying a germline mutation in ATF2 have a defect in endochondral ossification (Reimold et al., 1996). ATF2 regulates the expression of RB1, which regulates the G1- to S-phase transition by sequestering the E2F family members, necessary for cell cycle progression. When E2Fs are released, the cell is committed to progress through the cell cycle, which is essential in regulating cell proliferation vs differentiation.of chondrocytes and endochondral bone growth (Vale-Cruz et al., 2008).
ATF2/CREB1 binds to CRE domain of TNFSF11 (RANKL) promoter and TNFSF11 expression stimulates osteoclastogenesis in mouse stromal/osteoblast cells (Bai et al., 2005). Binding of JUN CREB1, ATF1, and ATF2 complexes are required for COL24A1 transcription, a marker of late osteoblast differentiation (Matsuo et al., 2006). Luteolin, a flavonoid, inhibits TNFSF11-induced osteoclastogenesis through the inhibition of ATF2 phosphorylation (Lee et al., 2009).
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ATF2 is expressed with large variations in intensity (and often highly expressed), according to the brain region examined.
Altogether, ATF2 seems to play a fundamental role in neuronal viability and in neurological functions in the normal brain and is down-regulated in the hippocampus and the caudate nucleus in Alzheimer, Parkinson and Huntington diseases (Pearson et al., 2005).
Mice carrying a germline mutation in ATF2 had a reduced number of cerebellar Purkinje cells, atrophic vestibular sense organs, an ataxic gait, hyperactivity,and decreased hearing (Reimold et al., 1996). A missense mutation in ATF2 in dogs has shown to provoke an autosomal recessive disease with short stature and weakness at birth, ataxia and generalized seizures, dysplastic foci consisting of clusters of intermixed granule and Purkinje cells, and death before 7 weeks of age (Chen et al., 2008d).
ATF2 plays critical roles for the expression of the TH gene (tyrosine hydroxylase) and for neurite extension of catecholaminergic neurons (Kojima et al., 2008).
Neuronal-specific ATF2 expression is required for embryonic survival, ATF2 has a strong pro-survival role in somatic motoneurons of the brainstem, and loss of functional ATF2 leads to hyperphosphorylated JNK and p38, and results in somatic and visceral motoneuron degeneration (Ackermann et al., 2011).
On the other hand, activated ATF2 promotes apoptosis of various brain cells, of which are cerebellar granule neurons (Ramiro-Cortés et al., 2011; Song et al., 2011). ATF2/JUN heterodimers bind and activate CASP3, a key executor of neuronal apoptosis, in cerebellar granule neurons (Song et al., 2011).
ATF2/JUN heterodimers bind and activate HRK (DP5, death protein 5/harakiri), a proapoptotic gene, promoting the death of sympathetic neurons (Ma et al., 2007; Towers et al., 2009), but also ATF2/JUN binds to two conserved CRE sites in the DUSP1 (MKP1) promoter; overexpression of DUSP1 inhibits JNK-mediated phosphorylation of JUN and protect sympathetic neurons from apoptosis (Kristiansen et al., 2010).
ATF2 overexpression in nucleus accumbens produces increases in emotional reactivity and antidepressant-like responses (Green et al., 2008), see Table 1.
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Table 1. Induction of activating transcription factors in the nucleus accumbens and their regulation of emotional behavior. (from Green et al., 2008).
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Skin and skin cancers
Inhibition of ATF2 with increased JNK/JUN and JUND induces apoptosis of melanoma cells (Bhoumik et al., 2004). MITF downregulation is mediated by ATF2/JUNB-dependent suppression of SOX10 transcription (Shah et al., 2010); MITF is a transcription factor for tyrosinase (TYR) and plays a role in melanocyte development.
ATF2 attenuates melanoma susceptibility to apoptosis. ATF2 control of melanoma development is mediated through its negative regulation of SOX10 and consequently of MITF transcription. The ratio of nuclear ATF2 to MITF expression is associated with poor prognosis (Shah et al., 2010). Assignment to the low-risk group in stage II melanoma requires elevated levels of overall CTNNB1 (beta-catenin) and nuclear CDKN1A (p21WAF1), decreased levels of fibronectin, and distributions that favor nuclear concentration for CDKN2A (p16INK4A) but cytoplasmic concentration for ATF2 (Gould Rothberg et al., 2009).
Phosphorylated ATF2 (p-ATF2) is significantly overexpressed in cutaneous angiosarcoma (malignant tumor) and pyogenic granuloma (benign tumor) than in normal dermal vessels (Chen et al., 2008a); p-ATF2 is also overexpressed in cutaneous squamous cell carcinoma, Bowens disease, and basal cell carcinomas, as compared to its expression in normal skin (Chen et al., 2008b).
High levels of ATF2/JUN dimers induce autocrine growth and primary tumor formation of fibrosarcomas in the chicken (van Dam and Castellazzi, 2001). ATF2 mutant mice in which the ATM phosphoacceptor sites (S472/S480) were mutated (ATF2KI mice) are more sensitive to ionizing radiation IR, exhibit increased intestinal cell apoptosis, develop a higher number of low-grade skin tumors (papillomas, squamous cell carcinomas, spindle cell carcinomas) (Li et al., 2010). A decrease of nuclear ATF2 and high CTNNB1 (beta-catenin) expression is seen in squamous cell carcinoma and basal cell carcinoma, compared to normal skin, while the cytoplasmic ATF2 expression was not significantly different in cancer and normal skin (Bhoumik et al., 2008b).
A nuclear localization of ATF2 would be associated with its oncogenic properties, and a cytosolic localization with its tumor suppressor properties (Lau and Ronai, 2012).
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Soft tissue sarcomas
In human and murine synovial sarcoma cells with t(X;18)(p11.2;q11.2) and a hybrid SS18-SSX, BCL2 expression is increased, but other anti-apoptotic genes, including MCL1 and BCL2A1 are repressed via binding of ATF2 to the cAMP-responsive element (CRE) in the promoters of these genes (Jones et al., 2012).
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ATF2 was found to upregulate Fas/FasL in a human chronic myeloid leukemia cell line (Chen et al., 2009).
NFE2L2 (NRF2) is a transcription activator of the bZIP family which binds to antioxidant response elements (ARE) in the promoter regions of target genes in response to oxidative stress. NFE2L2 positively regulates the expression the AP-1 family proteins ATF2, JUN and FOS. NFE2L2/ARE pathway plays an important role in the induction of differentiation of myeloid leukemia cells by 1alpha,25-dihydroxyvitamin D3 (1,25D), a strong differentiation agent (Bobilev et al., 2011). A crosstalk between NFE2L2 and ATF2 has also been noted in prostate cancer cells (Nair et al., 2010).
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Breast cancer
The loss of one copy of p53 in ATF2+/- mice led to mammary tumor development, which supports the notion that ATF2 and p53 independently activate SERPINB5 and GADD45 expression (Maekawa et al., 2008).
ATF2/JUN mediate increased BIM expression in response to MAPK14 (p38alpha) signaling in cells detached from the extracellular matrix, indicating a contributing role for ATF2 in regulating acinar lumen formation, crucial for the development of mammary gland development, a function that may be crucial to its ability to suppress breast cancer. (Wen et al., 2011).
ATF2/JUN binds to a potential CRE element of FOXP3, and induces its expression. FOXP3 acts as a transcriptional repressor of oncogenes such as ERBB2 and SKP2, and is able to cause apoptosis of breast cancer cells. The use of this ATF2-FOXP3 pathway may be of potential interest in future therapeutic approach of breast cancer. (Liu et al., 2009).
Aggressive basal-like breast cancer cells exhibit high expression of FOSL1 (FRA1)/JUN dimers rather than ATF2/JUN dimers (Baan et al., 2010).
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Uterus cancer
In PTEN-deficient endometrial cancers (which represent 1/3 to 3/4 of endometrial cancers), ATF2 is activated, while ATF2 shows a reduced expression in PTEN-positive endometrial cancers (Xiao et al., 2010).
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Prostate cancer
Heparan-sulfate proteoglycans are required for maximal growth factor signaling in prostate cancer progression. HS2ST1 (heparan sulfate 2-O-sulfotransferase, 2OST) is essential for maximal proliferation and invasion. HS2ST1 is upregulated by ATF2 (Ferguson and Datta, 2011).
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Lung cancer
Patients with lung cancer showing high ANGPTL2 expression in cancer cells had a poor prognosis. ANGPTL2 increases tumor angiogenesis, enhances tumor cell motility and invasion in an autocrine/paracrine manner, conferring an aggressive metastatic tumor phenotype. NFATc (NFATC1 to NFATC4 and NFAT5) function in tumor cell development and metastasis. It has been found that NFATc form a complex with ATF2/JUN heterodimers that bind to the CRE site of ANGPTL2 and enhances ANGPTL2 expression (Endo et al., 2012).
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Other cancers
Increased expression of ATF2 and ATF1 in nasopharyngeal carcinoma cells was associated with clinical stages (Su et al., 2011).


Pubmed IDLast YearTitleAuthors
215330462011Loss of ATF2 function leads to cranial motoneuron degeneration during embryonic mouse development.Ackermann J et al
170360532006Epigenetic determination of a cell-specific gene expression program by ATF-2 and the histone variant macroH2A.Agelopoulos M et al
188020552008Promoter analysis reveals critical roles for SMAD-3 and ATF-2 in expression of IL-23 p19 in macrophages.Al-Salleeh F et al
219011372011Coordinated regulation of ATF2 by miR-26b in γ-irradiated lung cancer cells.Arora H et al
166010712006The role of c-Jun N-terminal kinase, p38, and extracellular signal-regulated kinase in insulin-induced Thr69 and Thr71 phosphorylation of activating transcription factor 2.Baan B et al
157311152005Reactive oxygen species stimulates receptor activator of NF-kappaB ligand expression in osteoblast.Bai XC et al
156918752005Identification of human myometrial target genes of the c-Jun NH2-terminal kinase (JNK) pathway: the role of activating transcription factor 2 (ATF2) and a novel spliced isoform ATF2-small.Bailey J et al
119323062002Characterization and functional analysis of cAMP response element modulator protein and activating transcription factor 2 (ATF2) isoforms in the human myometrium during pregnancy and labor: identification of a novel ATF2 species with potent transactivation properties.Bailey J et al
121180742002p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration.Bakin AV et al
99900411999Identification of the cyclin D1 gene as a target of activating transcription factor 2 in chondrocytes.Beier F et al
182275162008Suppressor role of activating transcription factor 2 (ATF2) in skin cancer.Bhoumik A et al
112348882001Activating transcription factor 2-derived peptides alter resistance of human tumor cell lines to ultraviolet irradiation and chemical treatment.Bhoumik A et al
150105352004Transcriptional switch by activating transcription factor 2-derived peptide sensitizes melanoma cells to apoptosis and inhibits their tumorigenicity.Bhoumik A et al
179354922007ATF2 on the double - activating transcription factor and DNA damage response protein.Bhoumik A et al
186770982008ATF2: a transcription factor that elicits oncogenic or tumor suppressor activities.Bhoumik A et al
183978842008Regulation of TIP60 by ATF2 modulates ATM activation.Bhoumik A et al
159169642005ATM-dependent phosphorylation of ATF2 is required for the DNA damage response.Bhoumik A et al
220820052012Induction of group IVC phospholipase A2 in allergic asthma: transcriptional regulation by TNFα in bronchoepithelial cells.Bickford JS et al
210993662011The Nrf2 transcription factor is a positive regulator of myeloid differentiation of acute myeloid leukemia cells.Bobilev I et al
172674042007ATF2 is required for amino acid-regulated transcription by orchestrating specific histone acetylation.Bruhat A et al
150240922004p38 mitogen-activated protein kinase is the central regulator of cyclic AMP-dependent transcription of the brown fat uncoupling protein 1 gene.Cao W et al
196702682009JNK1/c-Jun and p38 alpha MAPK/ATF-2 pathways are responsible for upregulation of Fas/FasL in human chronic myeloid leukemia K562 cells upon exposure to Taiwan cobra phospholipase A2.Chen KC et al
197800382010Calcium-stimulated mitogen-activated protein kinase activation elicits Bcl-xL downregulation and Bak upregulation in notexin-treated human neuroblastoma SK-N-SH cells.Chen KC et al
93103691997Rapid induction of the Grp78 gene by cooperative actions of okadaic acid and heat-shock in 9L rat brain tumor cells--involvement of a cAMP responsive element-like promoter sequence and a protein kinase A signaling pathway.Chen KD et al
178694872008Overexpression of phosphorylated ATF2 and STAT3 in eccrine porocarcinoma and eccrine poroma.Chen SY et al
180741592008A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2.Chen X et al
97129021998Activating transcription factor-2 regulates phosphoenolpyruvate carboxykinase transcription through a stress-inducible mitogen-activated protein kinase pathway.Cheong J et al
117132762001TIP49b, a regulator of activating transcription factor 2 response to stress and DNA damage.Cho SG et al
76241511995Heterodimerization of c-Jun with ATF-2 and c-Fos is required for positive and negative regulation of the human urokinase enhancer.De Cesare D et al
218580822011A cytoplasmic negative regulator isoform of ATF7 impairs ATF7 and ATF2 phosphorylation and transcriptional activity.Diring J et al
223451522012Tumor cell-derived angiopoietin-like protein ANGPTL2 is a critical driver of metastasis.Endo M et al
97106251998Stress-induced Fas ligand expression in T cells is mediated through a MEK kinase 1-regulated response element in the Fas ligand promoter.Faris M et al
221357482011Role of heparan sulfate 2-o-sulfotransferase in prostate cancer cell proliferation, invasion, and growth factor signaling.Ferguson BW et al
94887271998Association of activating transcription factor 2 (ATF2) with the ubiquitin-conjugating enzyme hUBC9. Implication of the ubiquitin/proteasome pathway in regulation of ATF2 in T cells.Firestein R et al
102070541999Ubiquitination and degradation of ATF2 are dimerization dependent.Fuchs SY et al
107775452000Stability of the ATF2 transcription factor is regulated by phosphorylation and dephosphorylation.Fuchs SY et al
198845462009Melanoma prognostic model using tissue microarrays and genetic algorithms.Gould Rothberg BE et al
183052372008Induction of activating transcription factors (ATFs) ATF2, ATF3, and ATF4 in the nucleus accumbens and their regulation of emotional behavior.Green TA et al
78249381995Transcription factor ATF2 regulation by the JNK signal transduction pathway.Gupta S et al
18272031991Cross-family dimerization of transcription factors Fos/Jun and ATF/CREB alters DNA binding specificity.Hai T et al
25168271989Transcription factor ATF cDNA clones: an extensive family of leucine zipper proteins able to selectively form DNA-binding heterodimers.Hai TW et al
219537642012Berberine inhibits pulmonary metastasis through down-regulation of MMP in metastatic B16F-10 melanoma cells.Hamsa TP et al
212783802011ATF2 interacts with beta-cell-enriched transcription factors, MafA, Pdx1, and beta2, and activates insulin gene transcription.Han SI et al
199403602009Fas-induced apoptosis of renal cell carcinoma is mediated by apoptosis signal-regulating kinase 1 via mitochondrial damage-dependent caspase-8 activation.Hassan M et al
155466132004Identification of promoters bound by c-Jun/ATF2 during rapid large-scale gene activation following genotoxic stress.Hayakawa J et al
109805992000Autoamplification of apoptosis following ligation of CD95-L, TRAIL and TNF-alpha.Herr I et al
222753542012Critical role of N-terminal end-localized nuclear export signal in regulation of activating transcription factor 2 (ATF2) subcellular localization and transcriptional activity.Hsu CC et al
127892912003Death receptors and melanoma resistance to apoptosis.Ivanov VN et al
120528882002JDP2, a repressor of AP-1, recruits a histone deacetylase 3 complex to inhibit the retinoic acid-induced differentiation of F9 cells.Jin C et al
227970742013SS18-SSX2 and the mitochondrial apoptosis pathway in mouse and human synovial sarcomas.Jones KB et al
187723972008Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.Jones S et al
23200021990A cDNA for a human cyclic AMP response element-binding protein which is distinct from CREB and expressed preferentially in brain.Kara CJ et al
175900162007Multiple roles for acetylation in the interaction of p300 HAT with ATF-2.Karanam B et al
94369831998p300 and ATF-2 are components of the DRF complex, which regulates retinoic acid- and E1A-mediated transcription of the c-jun gene in F9 cells.Kawasaki H et al
16410041992Retinoblastoma gene product activates expression of the human TGF-beta 2 gene through transcription factor ATF-2.Kim SJ et al
178967922008Increased expression of tyrosine hydroxylase and anomalous neurites in catecholaminergic neurons of ATF-2 null mice.Kojima M et al
207027112010Mkp1 is a c-Jun target gene that antagonizes JNK-dependent apoptosis in sympathetic neurons.Kristiansen M et al
223049202012PKCε promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria.Lau E et al
226853332012ATF2 - at the crossroad of nuclear and cytosolic functions.Lau E et al
201623522009Inhibitory effect of luteolin on osteoclast differentiation and function.Lee JW et al
207400502010Radiation Sensitivity and Tumor Susceptibility in ATM Phospho-Mutant ATF2 Mice.Li S et al
85982831996Intramolecular inhibition of activating transcription factor-2 function by its DNA-binding domain.Li XY et al
201789802010cAMP/CREB-mediated transcriptional regulation of ectonucleoside triphosphate diphosphohydrolase 1 (CD39) expression.Liao H et al
171589552006JunB is required for endothelial cell morphogenesis by regulating core-binding factor beta.Licht AH et al
205629142010Cell transformation by v-Rel reveals distinct roles of AP-1 family members in Rel/NF-kappaB oncogenesis.Liss AS et al
165115682006Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization.Liu H et al
195842702009Activating transcription factor 2 and c-Jun-mediated induction of FoxP3 for experimental therapy of mammary tumor in the mouse.Liu Y et al
77371291995ATF-2 contains a phosphorylation-dependent transcriptional activation domain.Livingstone C et al
200294252010Emerging roles of ATF2 and the dynamic AP1 network in cancer.Lopez-Bergami P et al
174288072007dp5/HRK is a c-Jun target gene and required for apoptosis induced by potassium deprivation in cerebellar granule neurons.Ma C et al
172194132007Activating transcription factor 2 controls Bcl-2 promoter activity in growth plate chondrocytes.Ma Q et al
103642251999Mouse ATF-2 null mutants display features of a severe type of meconium aspiration syndrome.Maekawa T et al
177005202008ATF-2 controls transcription of Maspin and GADD45 alpha genes independently from p53 to suppress mammary tumors.Maekawa T et al
170547222006Sin1 binds to both ATF-2 and p38 and enhances ATF-2-dependent transcription in an SAPK signaling pathway.Makino C et al
163733412006CREB-AP1 protein complexes regulate transcription of the collagen XXIV gene (Col24a1) in osteoblasts.Matsuo N et al
115358122001Distinct effects of cAMP and mitogenic signals on CREB-binding protein recruitment impart specificity to target gene activation via CREB.Mayr BM et al
100924621999Solution structure of the transactivation domain of ATF-2 comprising a zinc finger-like subdomain and a flexible subdomain.Nagadoi A et al
207298722010Regulation of Nrf2- and AP-1-mediated gene expression by epigallocatechin-3-gallate and sulforaphane in prostate of Nrf2-knockout or C57BL/6J mice and PC-3 AP-1 human prostate cancer cells.Nair S et al
78432871995Down-regulation of the cyclin A promoter in differentiating human embryonal carcinoma cells is mediated by depletion of ATF-1 and ATF-2 in the complex at the ATF/CRE site.Nakamura T et al
121105902002Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38.Ouwens DM et al
158788072005Activating transcription factor 2 expression in the adult human brain: association with both neurodegeneration and neurogenesis.Pearson AG et al
223675042012Regulation of phosphatase and tensin homolog on chromosome 10 in response to hypoxia.Qian J et al
216831522011Reactive oxygen species participate in the p38-mediated apoptosis induced by potassium deprivation and staurosporine in cerebellar granule neurons.Ramiro-Cortés Y et al
111578572001Decreased immediate inflammatory gene induction in activating transcription factor-2 mutant mice.Reimold AM et al
217034492011Inheritance of stress-induced, ATF-2-dependent epigenetic change.Seong KH et al
151054252004Human vaccinia-related kinase 1 (VRK1) activates the ATF2 transcriptional activity by novel phosphorylation on Thr-73 and Ser-62 and cooperates with JNK.Sevilla A et al
212034912010A role for ATF2 in regulating MITF and melanoma development.Shah M et al
95117281998Activation of the rat cyclin A promoter by ATF2 and Jun family members and its suppression by ATF4.Shimizu M et al
219964232011Caspase-3 is a target gene of c-Jun:ATF2 heterodimers during apoptosis induced by activity deprivation in cerebellar granule neurons.Song B et al
18298051991Expression of the CRE-BP1 transcriptional regulator binding to the cyclic AMP response element in central nervous system, regenerating liver, and human tumors.Takeda J et al
193047502009The proapoptotic dp5 gene is a direct target of the MLK-JNK-c-Jun pathway in sympathetic neurons.Towers E et al
186385492008Activating transcription factor-2 affects skeletal growth by modulating pRb gene expression.Vale-Cruz DS et al
219804322011Transcriptional networks in epithelial-mesenchymal transition.Venkov C et al
118365642002Infrequent mutations of the activating transcription factor-2 gene in human lung cancer, neuroblastoma and breast cancer.Woo IS et al
201819292010Induced ATF-2 represses CDK4 transcription through dimerization with JunD inhibiting intestinal epithelial cell growth after polyamine depletion.Xiao L et al
200876032010Differential sensitivity of human endometrial carcinoma cells with different PTEN expression to mitogen-activated protein kinase signaling inhibits and implications for therapy.Xiao L et al
221095622012The effect of JDP2 and ATF2 on the epithelial-mesenchymal transition of human pancreatic cancer cell lines.Xu Y et al
191765252009Phosphorylation of Activation Transcription Factor-2 at Serine 121 by Protein Kinase C Controls c-Jun-mediated Activation of Transcription.Yamasaki T et al
213783962011Cellular iron depletion stimulates the JNK and p38 MAPK signaling transduction pathways, dissociation of ASK1-thioredoxin, and activation of ASK1.Yu Y et al
192551422009Opposing roles for ATF2 and c-Fos in c-Jun-mediated neuronal apoptosis.Yuan Z et al
114023402001Distinct roles of Jun : Fos and Jun : ATF dimers in oncogenesis.van Dam H et al

Other Information

Locus ID:

NCBI: 1386
MIM: 123811
HGNC: 784
Ensembl: ENSG00000115966


dbSNP: 1386
ClinVar: 1386
TCGA: ENSG00000115966


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
MAPK signaling pathwayKEGGhsa04010
Influenza AKEGGko05164
Influenza AKEGGhsa05164
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Dopaminergic synapseKEGGko04728
Dopaminergic synapseKEGGhsa04728
Cocaine addictionKEGGhsa05030
Cocaine addictionKEGGko05030
Amphetamine addictionKEGGhsa05031
Amphetamine addictionKEGGko05031
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hepatitis BKEGGhsa05161
Insulin secretionKEGGhsa04911
Estrogen signaling pathwayKEGGhsa04915
Estrogen signaling pathwayKEGGko04915
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Thyroid hormone synthesisKEGGhsa04918
Thyroid hormone synthesisKEGGko04918
Adrenergic signaling in cardiomyocytesKEGGhsa04261
Adrenergic signaling in cardiomyocytesKEGGko04261
cGMP-PKG signaling pathwayKEGGhsa04022
cGMP-PKG signaling pathwayKEGGko04022
Glucagon signaling pathwayKEGGhsa04922
Glucagon signaling pathwayKEGGko04922
Organelle biogenesis and maintenanceREACTOMER-HSA-1852241
Mitochondrial biogenesisREACTOMER-HSA-1592230
Transcriptional activation of mitochondrial biogenesisREACTOMER-HSA-2151201
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 10 (TLR10) CascadeREACTOMER-HSA-168142
MyD88 cascade initiated on plasma membraneREACTOMER-HSA-975871
MAP kinase activation in TLR cascadeREACTOMER-HSA-450294
MAPK targets/ Nuclear events mediated by MAP kinasesREACTOMER-HSA-450282
Activation of the AP-1 family of transcription factorsREACTOMER-HSA-450341
Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
Toll Like Receptor 5 (TLR5) CascadeREACTOMER-HSA-168176
Toll Like Receptor 7/8 (TLR7/8) CascadeREACTOMER-HSA-168181
MyD88 dependent cascade initiated on endosomeREACTOMER-HSA-975155
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activationREACTOMER-HSA-975138
Toll Like Receptor 9 (TLR9) CascadeREACTOMER-HSA-168138
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
MyD88:Mal cascade initiated on plasma membraneREACTOMER-HSA-166058
Toll Like Receptor 2 (TLR2) CascadeREACTOMER-HSA-181438
Toll Like Receptor TLR1:TLR2 CascadeREACTOMER-HSA-168179
Toll Like Receptor TLR6:TLR2 CascadeREACTOMER-HSA-168188
Gene ExpressionREACTOMER-HSA-74160
Generic Transcription PathwayREACTOMER-HSA-212436
Transcriptional Regulation by TP53REACTOMER-HSA-3700989
Circadian ClockREACTOMER-HSA-400253
Chromatin organizationREACTOMER-HSA-4839726
Chromatin modifying enzymesREACTOMER-HSA-3247509
HATs acetylate histonesREACTOMER-HSA-3214847
Aldosterone synthesis and secretionKEGGhsa04925
Aldosterone synthesis and secretionKEGGko04925
Longevity regulating pathwayKEGGhsa04211
TP53 Regulates Transcription of DNA Repair GenesREACTOMER-HSA-6796648

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA445210Pain, PostoperativeDiseaseClinicalAnnotationassociatedPD30106255


Pubmed IDYearTitleCitations
180774262007Runs of homozygosity reveal highly penetrant recessive loci in schizophrenia.131
146309182004Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation.94
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
121105902002Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38.65
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
159169642005ATM-dependent phosphorylation of ATF2 is required for the DNA damage response.59
126636702003The activation of c-Jun NH2-terminal kinase (JNK) by DNA-damaging agents serves to promote drug resistance via activating transcription factor 2 (ATF2)-dependent enhanced DNA repair.47
172446832007Prolonged shear stress and KLF2 suppress constitutive proinflammatory transcription through inhibition of ATF2.46
164181682006Up-regulation of PTEN (phosphatase and tensin homolog deleted on chromosome ten) mediates p38 MAPK stress signal-induced inhibition of insulin signaling. A cross-talk between stress signaling and insulin signaling in resistin-treated human endothelial cells.45
186770982008ATF2: a transcription factor that elicits oncogenic or tumor suppressor activities.41


Jean-Loup Huret

ATF2 (activating transcription factor 2)

Atlas Genet Cytogenet Oncol Haematol. 2012-10-01

Online version:

Historical Card

2007-07-01 ATF2 (activating transcription factor 2) by  Pedro A Lazo,Ana Sevilla 

Instituto de Biologia Molecular y Celular del Cancer, CSIC-Universidad de Salamanca, Salamanca, Spain